About 50% of all cases of childhood hearing loss are genetic in origin. Recent advances in molecular genetics enable the isolation and characterization of genes which influence the hearing process thus enhancing diagnostic accuracy, improving genetic counseling, and potentially leading to more effective methods of therapy. Importantly, the knowledge gained from these studies will provide a foundation for better understanding of the molecular biology of the auditory system. Progression from localization to the study of the expression of an individual gene requires a highly integrated research program. This institution has assembled the staff and facilities required to carry out all stages of the process and is now building upon the experience gained in the first cycle of the current Program Project. This renewal application proposes 5 related projects which will advance understanding of several human genetic disorders related to hearing. Continuation will help maintain existing external professional relationships and will foster further collaboration within an already successful and integrated team of scientists. This Program Project Grant has 5 research projects and 2 cores. Project 1 will study the role of a novel subfamily of K+ channel genes in the cochlea. Project 2 will continue with the construction and characterization of an Alport syndrome mouse. Project 3 will determine the frequency of linked nonsyndromic recessive hearing loss genes in the USA and will localize novel genes uncovered in the project. Project 4 continues work on physical mapping of Usher syndrome type II. Project 5 continues work toward the identification of the Branchio-oto-renal gene. Two cores are also proposed, Administrative/Clinical and Technical. This PPG brings together diverse investigators to meet a common goal: the further understanding of the molecular genetic basis of normal and abnormal hearing. It has already fostered close collaborations and promises continued productive collaborations in the future. The potentially collaborative value of the work is particularly attractive when viewed in context of the location of the project: BTNRH has existing auditory research programs that can take full advantage of the research proposed in this grant.